Calmodulin Regulates Ca2+-Dependent Feedback Inhibition of Store-Operated Ca2+ Influx by Interaction with a Site in the C Terminus of TrpC1

Abstract The mechanism involved in [Ca 2+ ] i -dependent feedback inhibition of store-operated Ca 2+ entry (SOCE) is not yet known. Expression of Ca 2+ -insensitive calmodulin (Mut-CaM) but not wild-type CaM increased SOCE and decreased its Ca 2+ -dependent inactivation. Expression of TrpC1 lacking C terminus aa 664–793 (TrpC1ΔC) also attenuated Ca 2+ -dependent inactivation of SOCE. CaM interacted with endogenous and expressed TrpC1 and with GST-TrpC1 C terminus but not with TrpC1ΔC. Two CaM binding domains, aa 715–749 and aa 758–793, were identified. Expression of TrpC1Δ758–793 but not TrpC1Δ715–749 mimicked the effects of TrpC1ΔC and Mut-CaM on SOCE. These data demonstrate that CaM mediates Ca 2+ -dependent feedback inhibition of SOCE via binding to a domain in the C terminus of TrpC1. These findings reveal an integral role for TrpC1 in the regulation of SOCE.